Pustular diseases and keratinocyte-myeloid synergy.

Pustules are among the most common lesions produced in human skin. Infections by pathogens and drug-induced reactions are frequent causes of pustule formation. In recent years immune-mediated pustular diseases have drawn attention. It is proposed to classify pustular diseases according to the initiating events and sites: purely epidermal pustules, follicular pustules or pustules noted in autoinflammatory syndromes. The unifying pathology in all of the three categories is a microinvasion of activated neutrophils into epidermal or adnexal epithelia. Formation of pustules involves established IL-17 / IL-23, IL-36 / IL-36RN driven pathology, or IL-1 /caspase-activated autoinflammation. Pathophysiology demonstrates an intriguing synergy of keratinocytes with neutrophils. This is called keratinocyte-myeloid synergy (KMS). Non-infectious pustules are formed by IFNα controlling the production of chemoattractants (IL-8, LTB4) or induced by IL-1-regulated inflammasomes and caspase/ IFNβ-induced chemotaxins. The presence of physical barriers, for example, cornified cell layers (str. corneum), is instrumental in establishing chemotactic gradients and blocking migrating neutrophils. In follicular KMS-driven pustular disorders, in contrast to epidermal pustules, neutrophil-mediated toxicity propagates lasting and expanding ulcerating diseases with increased levels of circulating immunoglobulin A (IgA). Complexed IgA is suggested to propagate ongoing pustular diseases. These are prerequisites essential for developing pustules in burdensome human skin diseases.